Not Applicable
Not Applicable
1. Field of the Invention
The present invention concerns new processes for the preparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
2. Description of the Related Art
The 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazole compounds of formula I 
or a pharmaceutically acceptable salt thereof, wherein:
R1, R2, R4, R5, R6, R8, R9, R12 and R13 are each independently hydrogen, alkyl, aryl or heteroaryl;
R3, R7, R10 and R11 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy; and
X is CH or N,
are novel, potent inhibitors of cyclin dependent kinases (cdks). They are useful in the therapy of proliferative diseases, for example, cancer, inflammation, autoimmune diseases such as arthritis, viral diseases, fungal diseases, chemotherapy-induced alopecia, neurodegenerative disorders such as Alzheimer""s disease and cardiovascular disease. More specifically, the compounds of formula I are useful in the treatment of a variety of cancers such as bladder, breast, colon, kidney, liver and lung cancers.
The preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles of formula I, has been described (K. S. Kim et al., WO 9924416, May 20, 1999 and corresponding U.S. Pat. No. 6,040,321).
4-Formylphenylacetic acid has been previously prepared from ethyl phenylacetate in four steps which provided  less than 15% overall yield (J. W. Baker et al., J. Chem. Soc. 1956, 404).
The reaction of 4-bromophenylacetic acid or ester with alkyl acrylates using palladium catalysts to give 4-(2-alkoxycarbonylvinyl)phenylacetic acid or ester has been previously reported in the literature (J. W. Tilley et al., J. Med. Chem. 1991, 34, 1125; A. Cerri et al., J. Heterocycl Chem. 1993, 30, 1581). The oxidation of xcex2-arylacrylates to give aryl aldehydes has also been reported (G. Cainelli et al., Synthesis, 1989, 47; D. G. Lee et al., Can. J. Chem. 1972, 50; D. G. Lee et al., Liebigs Ann. Chem. 1993, 503; S. Antus et al., Liebigs Ann. Chem. 1993, 105).
This invention concerns new efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs. The processes involve new strategy for the preparation of formylarylacetic acids, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
Not Applicable
The present invention relates to new, more efficient processes for the preparation of formylarylacetic acids with application to the synthesis of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs, inhibitors of cyclin dependent kinases. The processes involve reaction of haloarylacetic acids or esters II with olefins III to give vinylarylacetic acids or esters IV. Oxidation of IV with an oxidizing reagent gives formylarylacetic acids or esters V. Compared to the previous process which takes four steps and has yields less than 15%, the process of the invention can obtain the formylacetic acids or esters in only two steps and at substantially higher yields.
Subsequent coupling of formylarylacetic acids or esters V with 5-(2-oxazolylalkylthio)-2-aminothiazoles VI produces amides VII. Reductive amination of the amide VII with amines affords 5-(2-oxazolylalkylthio)-2-(aminoalkyl)arylacetylaminothiazoles I, inhibitors of cyclin dependent kinases.
Alternatively, compounds of formula I can be prepared by coupling of haloalkylarylacetic acids VIII with 5-(2-oxazolylalkylthio)-2-aminothiazoles VI followed by aminolysis of the resulting amides IX with amines.
The above-described reactions are illustrated in the below Scheme 1. 
In formulas I-IX of Scheme 1, the following terms apply:
R, R1, R2, R4, R5, R6, R8, R9, R12 and R13 are each independently hydrogen, alkyl, aryl or heteroaryl;
R3, R7, R10 and R11 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
W is halogen or sulfonate (RSO2Oxe2x80x94, CF3SO2Oxe2x80x94, etc.);
X is CH or N;
Y is CHO, C(O)R, COOR, CONRR1, CN, NO2, SO2OR or SO2NRR1; and
Z is hydrogen, CHO, C(O)R, COOR, CONRR1, CN, NO2, SO2OR or SO2NRR1.
Listed below are definitions of various terms used to describe the compounds involved in the processes of the present invention. These definitions apply to the terms as they are used throughout the specification (unless specifically indicated otherwise) either individually or as part of a larger group. It should be noted that any heteroatom with unsatisfied valences is assumed to have the hydrogen atom to satisfy the valences.
The term xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d (i.e., derivative forms of alkyl) refers to optionally substituted straight chain, branched or cyclic monovalent alkane (saturated hydrocarbon) derived radicals containing from 1 to 12 carbon atoms. When substituted, alkyl groups may be substituted with up to four substituent groups at any available point of attachment. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The alkyl can be optionally substituted with one or more halogens or alkyl groups such as, for example, trifluoromethyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, etc.
The term xe2x80x9carylxe2x80x9d or derivative forms thereof refers to monocyclic or bicyclic aromatic rings, e.g., phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like, containing from 6 to 30 carbon atoms. An aryl group can thus contain at least one ring having 6 atoms, with up to five such rings being present, containing up to 22 or 30 atoms therein, depending upon optionally alternating (resonating) double bonds between carbon atoms or suitable heteroatoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, biphenyl and the like.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to chlorine, bromine, fluorine or iodine, with bromine being the preferred halogen. The term xe2x80x9cheteroarylxe2x80x9d refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Exemplary heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrrolidinyl, piperidinyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrimidinal triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl, etc. The heteroaryl groups can be optionally substituted by one or more groups which include, but are not limited to, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkyloxycarbonyl, trifluoromethyl, cycloalkyl, nitro, cyano, amino, alkylS(O)m (where m=0, 1 or 2), thiol and the like.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to those salts of the biologically active compounds which do not significantly or adversely affect the pharmaceutical properties of the compounds, such as, for example, toxicity, efficacy, etc. and include those salts which are conventionally employed in the pharmaceutical industry. Suitable examples of salts include, but are not limited to, those formed with inorganic or organic acids such as hydrochloride, hydrobromide, sulfate, phosphate, etc. Also included, particularly for the intermediate compounds of the invention, are salts which are unsuitable for pharmaceutical utility but which can be employed otherwise, for example, for isolation or purification of free active compounds or their pharmaceutically acceptable salts.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of the compounds employed in the processes of the invention embraces all possible stereoisomers and their mixtures. The definition further embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods such as, for example, salt formation with an optically active acid followed by crystallization.
It should be understood that solvates (e.g., hydrates) of the compounds of formula I and the intermediate compounds are also within the scope of the present invention. Methods of solvation are generally known in the art. Therefore, the compounds useful in the processes of this invention may be in the free or hydrate form.
As set forth in Scheme 1, the process for the preparation of 5-(2-oxazolylalkylthio)-2-arylacetylaminothiazoles and analogs involves the following transformations:
(a) reacting a haloarylacetate II with an olefin III in the presence of a palladium catalyst in a suitable solvent or solvent mixtures to give a vinyl-substituted arylacetate IV such as vinylarylacetate.
It should be appreciated that the term xe2x80x9chaloarylacetatexe2x80x9d for purposes of the present invention includes both haloarylacetic acids and esters. Additionally, a sulfonate, for example, RSO2Oxe2x80x94 (where R is alkyl, aryl or heteroaryl), CF3SO2Oxe2x80x94 and the like, may be substituted for the halogen in the arylacetate or arylacetic acid starting compounds. The preferred haloarylacetates are haloarylacetic acids with bromophenylacetic acids, such as, for example, 4-bromophenylacetic acid, most preferred. The olefin includes alkenes and polymers derived from an alkene such as ethyl or methyl acrylate. The palladium catalysts include, but are not limited to, palladium acetate or diacetate, palladium halides, etc., with the palladium diacetate preferred. Other standard catalysts may be employed although less conveniently. A conventional ligand for the palladium catalyst such as trialkyl or triarylphosphine can also be employed. Suitable solvent(s) include solvents such as hydrocarbons, ethers, amides, for example, dimethylformamide (xe2x80x9cDMFxe2x80x9d), ketones, etc., or mixtures thereof, with amides such as DMF preferred.
(b) reacting the vinyl-substituted arylacetate IV, like vinylarylacetate, obtained in step (a) with an oxidizing reagent in a suitable solvent or solvent mixtures to give a formylarylacetate V.
The oxidizing reagent includes, but is not limited to, O3, KMnO4, NaIO4/OsO4, etc., with NaIO4/OsO4 preferred. Suitable solvent(s) include solvents such as hydrocarbons, ethers, esters, amides, and the like, mixtures thereof, or aqueous mixtures thereof, with an ether and water mixture preferred.
For example, the oxidative cleavage of the double bond of formula IV by a reagent such as osmium tetroxide with sodium periodate in a dioxane/water mixture gives the desired vinyl-substituted arylacetic acid or arylacetate, such as formylphenylacetic acid or formylphenylacetate.
(c) reacting the formylarylacetate V obtained in step (b) with a 5-(2-oxazolylalkylthio)-2-aminothiazole compound VI in the presence of a coupling reagent and in a suitable solvent or solvent mixtures to give an amide VII.
The 5-(2-oxazolylalkylthio)-2-aminothiazoles include 5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazole compounds with 5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole preferred. The coupling reagents include, but are not limited to, carbodiimides, haloformates, thionyl halide and the like, with thionyl halide preferred. Suitable solvent(s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, etc., with halogenated hydrocarbons such as dichloromethane preferred.
(d) reacting the amide VII obtained in step (c) with an amine in the presence of a reducing reagent in a suitable solvent or solvent mixtures to give 5-(2-oxazolylalkylthio)-2-(aminoalkyl)arylacetylaminothiazole I.
The amine used in reaction (d) includes primary and secondary amines with primary aliphatic amines preferred. The reducing reagents include, but are not limited to, NaBH4, NaBH(OAc)3, Et3SiH/TFA and the like with NaBH(OAc)3 preferred. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, etc., or mixtures thereof, with ethers such as tetrahydrofuran (xe2x80x9cTHFxe2x80x9d) preferred.
Alternatively, the compounds of formula I can be prepared by:
(cxe2x80x2) reacting the haloalkylarylacetate VIII with a 5-(2-oxazolylalkylthio)-2-aminothiazole compound VI in the presence of a coupling reagent and in a suitable solvent or solvent mixtures to give an amide IX.
The 5-(2-oxazolylalkylthio)-2-aminothiazoles include 5-(5-substituted-2-oxazolylalkylthio)-2-aminothiazole compounds with 5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole preferred. The coupling reagents include, but are not limited to, carbodiimides, haloformates, thionyl halide and the like, with the former preferred, for example, an alkylcarbodiimide. Suitable solvent(s) include aprotic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, esters, etc., with halogenated hydrocarbons such as dichloromethane preferred.
For instance, treatment of haloalkylarylacetate or haloalkylarylacetic acid VIII such as haloalkylphenylacetate or haloalkylphenylacetic acid with 5-(2-oxazolylalkylthio)-2-aminothiazole VI provides a haloalkyl-substituted phenylacetamide IX.
(dxe2x80x2) reacting the amide IX obtained in step (cxe2x80x2) with an amine in a suitable solvent or solvent mixtures to give 5-(2-oxazolylalkylthio)-2-(aminoalkyl)arylacetylaminothiazole
The amine used in reaction (dxe2x80x2) includes primary and secondary amines with primary aliphatic amines preferred. Suitable solvent(s) include hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, etc., with amides such as DMF preferred.
For example, the reaction under reductive amination conditions with a primary or secondary amine in the presence of sodium cyanoborohydride or hydrogen in the presence of a catalyst gives the compounds of formula I.
Alternatively, the aldehydes of formula VII may be reacted with an organometallic reagent such as methylmagnesium bromide in a suitable solvent or solvent mixture, such as, for example, ether to give an alcohol derivative. The alcohol derivative is converted to its corresponding halide such as a chloride by a chlorinating agent such as thionyl chloride. The halide compound such as the chloride compound may then be converted to a compound of formula I by reaction with an excess of a primary or secondary amine in a suitable solvent such as ethanol.
The starting compounds of Scheme 1 are commercially available or may be prepared by methods known to one of ordinary skill in the art.
To further illustrate Scheme 1, a process to make formylphenylacetic acids with application to the synthesis of 5-(5-t-butyl-2-oxazolylmethylthio)-2-[(aminomethyl)phenylacetyl]aminothiazoles and analogs thereof, for example, starts with the reaction of halophenylacetic acids II such as bromophenylacetic acid (Rxe2x95x90R1xe2x95x90R2xe2x95x90R3xe2x95x90H, Xxe2x95x90Br) with alkyl acrylate III such as ethyl acrylate (R4xe2x95x90Zxe2x95x90H, Yxe2x95x90CO2Et) to give (2-ethoxycarbonyl)vinylphenylacetic acids IV (Rxe2x95x90R1xe2x95x90R2xe2x95x90R3xe2x95x90R4xe2x95x90Zxe2x95x90H, Yxe2x95x90CO2Et). Oxidation of IV with a suitable oxidizing reagent gives formylphenylacetic acids V (Rxe2x95x90R1xe2x95x90R2xe2x95x90R3xe2x95x90R4xe2x95x90H). Coupling of V with 5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole VI (R6xe2x95x90R7xe2x95x90R8xe2x95x90R9xe2x95x90R10xe2x95x90H, R11xe2x95x90t-Bu) produces amides VII (R1xe2x95x90R2xe2x95x90R3xe2x95x90R4xe2x95x90R6xe2x95x90R7xe2x95x90R9xe2x95x90R10xe2x95x90H, R11xe2x95x90t-Bu). Reductive amination of VI amines affords 5-(5-t-butyl-2-oxazolylalkylthio)-2-(aminomethyl)phenylacetylaminothiazoles I, inhibitors of cyclin dependent kinases. Alternatively, compounds of formula I can be prepared by coupling of haloalkylphenylacetic acids VIII such as bromomethylphenylacetic acid (Rxe2x95x90R1xe2x95x90R2xe2x95x90R3xe2x95x90R4xe2x95x90R5xe2x95x90H) with 5-(5-t-butyl-2-oxazolylalkylthio)-2-aminothiazole VI followed by aminolysis of the resulting amides IX with amines.
The following examples demonstrate certain aspects of the present invention. However, it is to be understood that these examples are for illustration only and do not purport to be wholly definitive as to conditions and scope of this invention. It should be appreciated that when typical reaction conditions (e.g., temperature, reaction times, etc.) have been given, the conditions both above and below the specified ranges can also be used, though generally less conveniently. The examples are conducted at room temperature (about 23xc2x0 C. to about 28xc2x0 C.) and at atmospheric pressure. All parts and percents referred to herein are on a weight basis and all temperatures are expressed in degrees centigrade unless otherwise specified.